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Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase i inhibitors

a technology of topoisomerase and indenoisoquinoline, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocide, etc., can solve the problems of double-stranded dna breakage and apoptosis, and achieve potent top1 inhibitory activity

Active Publication Date: 2015-05-28
PURDUE RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about a series of compounds that can be used as anticancer agents. These compounds are made by adding alcohols, diols, and carbohydrates to indenoisoquinolines. These compounds have been tested in a panel of cancer cell lines and have shown activity against multiple types of cancer cells. They are also able to target a protein called Top1. These compounds can be used alone or in combination with other drugs to treat cancer. The invention also includes a method for increasing the activity of these compounds by adding a few extra atoms to the ring structure and replacing a primary alcohol with an amino group.

Problems solved by technology

As a result, it is believed that advancing replication forks collide with the cleavage complex, resulting in double-stranded DNA breaks and apoptosis.
Although these inhibitors are reported to possess potent antitumor activity, issues regarding solubility and bioactivity, dose-limiting toxicity, and importantly, the instability of the hydroxy lactone and associated pharmacokinetic liabilities, have reportedly led to the development of therapeutic alternatives.

Method used

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  • Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase i inhibitors
  • Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase i inhibitors
  • Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase i inhibitors

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examples

[0130]The following examples further illustrate specific embodiments of the invention; however, the following examples should not be interpreted in any way to limit the invention.

Example

[0131]Chemistry. Aldopentose and Aldohexose Substituents. In a previous publication, the installation of indenoisoquinoline side chains involving condensation of the indenoisochromenone lactone (a vinylogous anhydride, e.g. compound 16, Scheme 1) with a primary amine was reported. The preparation of carbohydrate-derived indenoisoquinolines followed a similar approach, by the conversion of the aldose into an aminodeoxyalditol. Without being bound by theory, it was speculated that protection of the hydroxyl groups of the monosaccharide may be necessary to carry out the required transformations. However, the published method of Winestock and Plaut for preparation of aminodeoxyalditols was employed without recourse to protecting groups.[Winestock, C. H., et al., J. Org. Chem. 1961, 26, 4456-4462] This me...

example

[0201]Modeling of Indenoisoquinolines. Indenoisoquinolines 12a and 12b were constructed in SYBYL. Hydrogens were added, and the ligands were minimized using either the MMFF94 force field with MMFF94 charges, or the Tripos force field with Gasteiger-Huckel charges. Each ligand (two per charge set, four total) was docked into the mutant crystal structure using GOLD 3.2 using default parameters and the coordinates defined by the crystal structure as described above. The top three poses for each ligand were examined, and both the normal (compounds 12a and 12b) and flipped (compound 12a only) ligands were merged into the crystal structure, and the entire complex was subsequently subjected to minimization using a standard Powell method, the MMFF94 force field and MMFF94s charges, a distance-dependant dielectric function, and a 0.05 kcal / mol*Å energy gradient convergence criterion. The ligand overlays in FIG. 2 were constructed by aligning the crystal structures of 1SC7 and 1SEU using the ...

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Abstract

The invention described herein pertains to substituted indenoisoquinoline compounds as described herein, wherein RA, RD, W, X and Y are defined herein, pharmaceutical compositions and formulations comprising the indenoisoquinoline compounds, their synthesis, and methods for their use in the treatment and / or prevention of cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Patent Application No. 61 / 489,900, filed May 25, 2011.GOVERNMENT RIGHTS[0002]This invention was made with government support under CA089566 awarded by the National Institutes of Health Research. The United States government has certain rights in this invention.TECHNICAL FIELD[0003]The invention described herein pertains to substituted indenoisoquinoline compounds, pharmaceutical compositions and formulations comprising the indenoisoquinoline compounds, their synthesis, and methods for their use in the treatment and / or prevention of cancer.BACKGROUND AND SUMMARY OF THE INVENTION[0004]Topoisomerase I (Top1) is an enzyme that is believed to relax supercoiled DNA. Relaxed DNA is reported to be required for many cellular processes such as DNA replication, transcription, and repair. Top1 is believed to relax DNA through a cycle of cleavage and religation steps involving the active site residue Tyr723....

Claims

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Application Information

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IPC IPC(8): C07D221/18
CPCC07D221/18A61P35/00C07D311/94
Inventor CUSHMAN, MARK S.POMMIER, YVES GEORGE
Owner PURDUE RES FOUND INC
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